7-[(3R,4R)-3-Hydroxy-4-hydroxymethyl-pyrrolidin-1-ylmethyl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one (Compound 1) inhibits a number of relevant enzymes is implicated in human disease, including, but not limited to, purine nucleoside phosphorylase. 7-[(3R,4R)-3-Hydroxy-4-hydroxymethyl-pyrrolidin-1-ylmethyl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one is currently being developed for the treatment of a number of human disease, including, but not limited to cancer, B and T-cell mediated disease, bacterial infections and protozoal infections. The use of Compound 1 is described in U.S. Pat. No. 7,553,839, which is hereby incorporated by reference for such teaching.
Many pharmaceutically acceptable salts of compound 1 are known in the literature. These include, but are not limited to, hydrochlorides, dihydrochorides, hydrobromides, hemisulfate, p-tosylate, phosphate, citrate, L-tartrate, L-lactate, stearate, maleate, succinate, fumarate, and L-malate.
While a number of salts of compound 1 have been described, many of described salt forms display properties that are not optimal. For example, the hydrochloride salt of compound 1 has been shown to contain polymorphic variants. In certain cases it may be desirable to obtain a salt of a pharmaceutical compound with no or a decreased number of polymorphic variants.
Mixed crystal salts are known in the literature (Kitaigorodsky, A. I., Solid Solutions, Springer-Verlag: Berlin, 1984). Mixed crystals are formed when a new molecular entity substitutes for another in a crystal structure without significantly disturbing the unit cell. When the proportion is adjustable in the mixed crystal, the material is also referred to as a solid solution. Most commonly, it is small anions and cations that can substitute for similar species in a crystal lattice. For example, nickel and manganese atoms can substitute for one another to form continuous isomorphic mixed crystals in the double salt 2RbCl.MCl2.2H2O, where M=Ni or Mn (J. Chem. Thermodynamics, 28, 743, 1996). Potassium can substitute for rubidium in arenesulfonates (Inorg. Chem., 22, 2924-2931, 1994) and a number of divalent metal ions substitute for one another in formates (J. Solid State Chem., 57, 260-266, 1985).
Less commonly, larger species, such as organic molecules, substitute for one another. For example, progesterones such as 11α-hydroxy-16α, 17α-epoxyprogesterone (HEP) and 16α,17α-epoxyprogesterone (EP) form isostructural mixed crystals up to a certain ratio (Ind. Eng. Chem. Res., 45, 432-437, 2006). Physiologically active sulfadimidine forms monoclinic crystals with either aspirin or 4-aminobenzoic acid and triclinic crystals with either 2-aminobenzoic acid or 4-aminosalicylic acid (Molecular Pharmaceutics., 4 (3), 310-316, 2007). Likewise, cis-itraconazole forms a series of salts with C4 acids (J. Am. Chem. Soc., 125, pp. 8456-8457) which may be isomorphic. U.S. Pat. No. 3,870,732 (1974) teaches that “mixed crystals” of aluminum and certain carboxylic acids can form although it is not clear if they are isomorphic structures.
Mixed salts offer the potential for physical properties that are different from those of the non-mixed salts alone and so can be helpful in many areas such as the manufacturing of drug products, whose suitability for use often hinges on the properties of the active pharmaceutical ingredient. Like unmixed salts, mixed salts are potentially polymorphic and some of these can be expected to be unstable. Therefore it is desirable to develop stable salts that will provide for the easy manufacture of salts of compound 1.
There is a need in the art to develop new salts of compound 1 with new properties. The present disclosure provides novel hemi- and mono-salt forms of compounds 1 and methods of synthesizing the same.